Influence of CYP2C9 and CYP2C19 genetic polymorphisms on phenytoin-induced neurological toxicity in Indian epileptic patients

Abstract

Cytochrome P450 2C9 and 2C19 (CYP2C9 and CYP2C19, respectively) genetic polymorphisms play an important role in phenytoin (PHT) metabolism. We have evaluated whether these genetic polymorphisms have an effect on PHT-induced neurological toxicity in Tamilian (ethnic group native to southern India) patients with epilepsy. We studied 292 Tamilian patients who were taking PHT for the treatment of various epileptic seizures. PHT toxicity was defined on the basis of neurological signs of toxicity and further sub-classified into mild, moderate, and severe toxicity based on clinical severity. Genomic DNA was extracted from peripheral leukocytes and genotyped for CYP2C9*2, *3 and CYP2C19*2, *3 by PCR-restriction fragment length polymorphism analysis. Of the 292 patients in the patient cohort, 58 were clinically diagnosed to have PHT toxicity. When risk ratios were calculated for each mutant CYP2C9 genotype separately, the adjusted odds ratio for CYP2C9*1/*3 was found to be 15.3 (95% confidence interval 5.8-40.3, P<0.0001) for the cases compared to controls. When the four single nucleotide polymorphisms of CYP2C9 and CYP2C19 were analyzed using a haplotype approach, significant difference in the distribution of the C-C-G-G haplotype was observed between the cases and controls. Our results show that CYP2C9 genetic polymorphisms (particularly the *3 allele) were associated with high risk of epileptic patients developing PHT-induced neurological toxicity.